An understanding of the propagation of electrical activity through ventricular myocardium requires knowledge of both the electrical behavior of an individual cardiac cell, and the role of the cardiac syncytium. This project will utilize electric, magnetic, and optical mapping of cardiac activation in the isolated rabbit heart and numerical simulations with the bidomain model to link ion channel kinetics to macroscopic electrical behavior. In the bidomain model, cardiac tissue is a three dimensional (3-D) electrical cable with anisotropic intra-and extracellular spaces that are separated by a nonlinear cell membrane. Recent experiments confirm the validity of this model with unequal intra- and extracellular anisotropies, and demonstrate the important role of virtual cathodes and anodes in the cardiac response to electrical stimulation. The objectives of this proposal are to explore poorly understood phenomena in cardiac electrophysiology that may be the result of unequal anisotropies, and to apply the resulting knowledge to problems in cardiac stimulation and defibrillation. The Specific Aims are to determine how electrical anisotropies and tissue macrostructure affect (1) the propagation of depolarization (2) the spread of repolarization, and (3) the response to external electrical stimuli. This will require (4) refinement of the advanced electrical, optical, and magnetic recording techniques and numerical methods already developed by the investigators, and may require (5) extension of the bidomain model to include tissue heterogeneities. Hypotheses to be tested include: a perfusing bath reduces the rate of rise of the action potential; the spiral fiber geometry at the cardiac apex produces electrically-silent magnetic fields; the MCG T-wave is altered at high heart rates whereas the MCG QRS, ECG QRS, and ECT T-wave are not; unequal bidomain anisotropies and tissue interfaces determine the magnitude fields from injury currents; anodal and cathodal strength-interval curves contain make and break sections; the dip in the anodal strength-interval curve corresponds to anodal-break stimulation; virtual electrodes are important in both bipolar and biphasic stimulation; a SQUID magnetometer array can image defibrillation currents; and cardiac fiber curvature strongly affects the transmembrane potential distribution during defibrillation. The required electrical and optical instruments are already developed; a scanning high resolution SQUID magnetometer array will be constructed for mapping the epicardial magnetic field of the isolated rabbit heart. This research could clarify the role of electrical anisotropy during propagation and repolarization, and during stimulation and defibrillation of the heart.